Innate and adaptive immunity constitute two distinct but functionally interrelated systems that collectively effect host responses to bacterial, viral and other pathogens. Further understanding the relative roles of these two major arms of immunity is confounded by their genetic complexity, interconnectivity and inherent limitations of studying early immunity in mammalian model systems. Zebrafish is a well-characterized genetic model system in which development is ex utero. Integral components of its immune system are structurally and functionally orthologous to those found in mammals. Unlike mammalian developmental immunology models, a temporal distinction exists in zebrafish in which a protracted period of innate immunity precedes the functional rearrangement of immunoglobulin (Ig) and T cell antigen receptor (TCR) genes and lymphocyte development, allowing the study of innate immune responses in relative isolation. In zebrafish as well as in humans and other mammals, complex families of Ig superfamily (IgSF) members are expressed on cells that mediate immune functions. Several such large families of diversified molecules, termed immune domain-containing receptors (IDCRs), have been identified in zebrafish and two families of these molecules are the focus of these investigations. The genomics of IDCRs will be characterized, transcripts will be recovered, their functional domains will be expressed, ligand-binding properties determined and the functional relevance of IDCRs to immune response evaluated. In order to accomplish these goals, a variety of platforms will be developed for functional characterization, including several approaches for detecting low affinity interactions. The continuing refinement of the zebrafish genome affords the possibility to target and genetically disrupt receptor functions using: 1) morpholino (including caged analogs)- based down regulation of individual receptors and 2) targeted disruption of specific genes through an efficient site-specific zinc finger nuclease-based enzymatic method, which affords rapid selection of recombination events. The roles of IgSF-related molecules in the innate immune response in early development will be studied using in vivo bacterial and viral disease-challenge models. The ubiquitous presence of large, diversified families of IgSF receptors throughout the vertebrates makes it likely that insight will be gained into how corresponding molecules function in immune protection in humans.